Method for reducing the severity of neurological disorders

ABSTRACT

The present invention relates to the use of
         polyunsaturated fatty acids and   one or more components which have a beneficial effect on total methionine   metabolism selected from the group consisting of vitamin B12 and precursors   thereof, vitamin B6 and derivatives thereof, folic acid, zinc and magnesium,
 
in the manufacture of a preparation for improving the action of receptors. This preparation is advantageously applied in patients suffering from Parkinson&#39;s disease, Huntington&#39;s chorea, epilepsy, schizophrenia, paranoia, depression, sleep disorders, impaired memory function, psychoses, dementia and ADHD.

This application is a divisional application of Ser. No. 12/045,112,filed Mar. 10, 2008, currently pending, which is a divisionalapplication of Ser. No. 10/495,341 filed May 13, 2004, which claimspriority to PCT/NL2002/00731, filed Nov. 14, 2002. The teachings of theabove applications are hereby incorporated by reference. Any disclaimerthat may have occurred during prosecution of the above referencedapplications is hereby expressly disclaimed.

The present invention relates to a preparation for improving the actionof receptors, in particular for improving the sensitivity of receptorsto neurotransmitters.

Receptors can be present in the membranes of cells. The receptor isactivated under the influence of components present outside the cell(for example, neurotransmitters, neuromodulators or hormones) which bindto the receptor. The receptor is then capable of transmitting signals,which can start a cascade of events. Receptors can be present, interalia, in or on nerve cells, muscle cells, endocrine cells, epithelialcells or other types of cells. Examples of substances which have aneffect on receptors are neurotransmitters (see below), neuromodulators,neuropeptides and hormones such as insulin and steroids.

A specific class of receptors is, for example, constituted by receptorsin nerve cells (neurones) which are controlled by neurotransmitters.These neurones consist of a cell body (soma) with several, frequentlyshort fimbriae (dendrites) and one long fimbria, termed an axon. Anelectrical signal is transmitted from the soma via the axon. The axonbranches into axon ends which can terminate next to the dendrites ofadjacent nerve cells, onto another axon, next to the soma of nerve cellsor in tissues or parts thereof. The so-called synaptic cleft is locatedbetween the axon of the one nerve cell and the dendrite (or also soma)of the other nerve cell.

If a nerve cell is stimulated, substances can be released which aretermed neurotransmitters or neuromodulators and which are able toactivate another nerve cell. The neuro-transmitters/neuromodulators arerecognised by receptors in the postsynaptic membrane of the “receiving”nerve cell.

Examples of classic endogenous neurotransmitters are biogenic aminessuch as serotonin, dopamine, histamine, noradrenaline and adrenaline;amino acids such as GABA (gamma-aminobutyric acid), glutamate, aspartateand glycine; cholinergic agents, such as acetylcholine; peptides, suchas endorphins and other types of neurotransmitters such as nitrogenoxide and adenosine. In addition, many substances have been found whichare recognised by the neurotransmitter receptors, such as certain drugs(for example clenbuterol), which usually are prepared synthetically, butalso substances from natural preparations (such as muscarine antagonistsor ephedrine-rich plant extracts).

Receptors can be classified on the basis of their action. Ionotropicreceptors act rapidly and determine ion transport through the membrane.They consist of a large complex of multiple sub-units made up of fiveindividual proteins which combine to establish an ion channel throughthe membrane. The sub-units have four transmembrane domains which formthe pore. These ion channels are impermeable to ions in the absence of aneurotransmitter.

Metabotropic receptors constitute another class. These act relativelyslowly and have a wide range of effects on the metabolism of the cell.Many comprise the seven trans-membrane domain receptors, which usuallyfunction via G proteins. These types of receptors play a role, interalia, in the case of neurotransmitters which belong to the adrenergicagents (for example noradrenaline and adrenaline), in the case ofdopamine, serotonin and in the case of neurotransmitters which belong tothe cholinergic agents (such as acetylcholine or muscarine). Otherexamples of seven transmembrane domain receptors are receptors which areactivated by neuropeptides, such as by Substance P, Neuropeptide Y,Bombesine, Neurotensine, CCK and galanine.

Others include single transmembrane domain receptors such as thetyrosine kinase receptor family (growth factors, insulin), the cytokinereceptor family (growth hormone, erythropoietin, leptin, prolactin), theserine-threonine kinase receptor family (TGF-beta), the guanylyl cyclasereceptor family (atrial natriuretic peptides) and the phosphotyrosinephosphatase family.

Many medical disorders are associated with disturbed signaltransmission. This can be due to a reduced concentration of hormonesand/or neurotransmitters and/or neuromodulators, but also to a reducedsensitivity of the receptor towards the specific substance.

A neurotransmitter functioning that is disturbed to a more or lesssevere extent can play a role in neurological disorders such asdementia, depression, Parkinson's disease, Huntington's chorea,epilepsy, schizophrenia, paranoia and ADHD, but also in other emotionaldisorders.

Various ways for improving the functioning of the nerve processes havebeen conceived in the past. For example, neurotransmitters such asdopamine or derivatives thereof have been administered to peoplesuffering from Parkinson's disease in order to increase the amount ofdopamine in the synapse. Substances have also been administered in orderto reduce the reuptake of the neurotransmitter serotonin from thesynaptic cleft into the dendrite. Agents which inhibit a specificmetabolic conversion of the neurotransmitter acetylcholine(acetylcholinesterase inhibitors), as a result of which theconcentrations of acetylcholine in the synaptic cleft (i.e.extracellular) remain high for a prolonged period, have also beendescribed. Monoamine oxidase inhibitors partially prevent the conversionof monoamines such as dopamine.

In contrast with the aforementioned approaches, the aim of the inventionis to improve the action, and especially the sensitivity of receptors,in particular in nerve processes, but also in other physiologicalprocesses in which, for example, hormones play a role. What is meant byan improved action of receptors is that less agonist, in particular lessneurotransmitter, is needed to achieve the same effect. The presentinvention may advantageously be applied in patients who suffer from animbalanced neurotransmitter functioning and/or neurodegenerativedisorder. In addition, the invention may be applied in healthyindividuals to improve the concentration and/or learning ability ofthese individuals.

The invention relates to the use of

-   -   polyunsaturated fatty acids and    -   components which have a beneficial effect on methionine        metabolism for improving the action of receptors.

The inventors have unexpectedly found that the combined application ofpolyunsaturated fatty acids and methionine metabolism stimulatingcompounds improves the action of receptors, but not as a result of theincreased production of neurotransmitter or a reduced reuptake ofneurotransmitter from the synaptic cleft. According to the inventors,the surprising effect of the active principles according to theinvention may be explained from the improved arrangement and more fluidnature of the cell membranes, especially of the membranes of neurons,that results from the combined administration. Because of the improvedarrangement and fluidity, in vivo membrane processes can proceed moreeffectively after receptor activation. This improvement is not onlyadvantageous in individuals in whom these membrane processes areadversely affected by, for instance, a neurodegenerative disorder. Theimprovement is also beneficial to individuals who wish to improve theirability to learn and/or concentrate, e.g. for study or work.

The treatment of a variety of disorders, including neurodegenerativedisorders such as Alzheimer disease and Parkinson's disease withpolyunsaturated fatty acids and vitamin B6, B12 and/or folic acid isdescribed in WO 01/03696. In this PCT-application a link is made betweenan elevated serum homocysteine concentration and the undesired oxidationof essential fatty acids, in particular of eicosapentenoic acid andarachidonic acid. The administration of vitamin B6, folic acid andvitamin B12 is said to decrease the serum homocysteine concentration andconsequently to diminish the oxidation of the aforementioned essentialfatty acids, as a result of which, in combination with theadministration of these same essential fatty acids, an increase in theserum concentration of these essential fatty acids is achieved.According to the PCT-application an increase of the concentration ofessential fatty acids can be advantageous in the treatment of (a)illnesses, (b) cardiovascular or cerebrovascular disorders, (c)diabetes, syndrome X and macro or microvascular complications ofdiabetes, (d) psychiatric disorders, (e) neurological orneurodegenerative disorders, (f) kidney disorders, (g) inflammatory orimmunological disorders of the gastrointestinal tract, (h) eye orhearing disorders, (i) forms of obesity and (j) any form of cancer.Nowhere in the PCT-application reference is made to an effect of thepreparations described therein on receptor action.

Suppletion with the preparation according to the invention is beneficialin those situations where the endogenous production of neurotransmittersis marginal but the receptor is still functional, as is the case forminor manifestations of neurological disorders.

In persons suffering from serious forms of neurological disorders it isadvantageous that, in addition to the aforementioned components, atleast one substance is administered that increases the concentration ofthe neurotransmitters, neuromodulators or hormone in the synapse or atthe receptor.

Polyunsaturated fatty acids are fatty acids containing at least twounsaturated bonds and having a chain length of at least 18. Theunsaturated bond is located in the 3, 6 or 9 position relative to theterminal methyl group.

The preparation of the invention preferably contains Ω-3 polyunsaturatedfatty acids. The Ω-3 polyunsaturated fatty acids include α-linolenicacid, stearidonic acid, eicosapentaenoic acid and docosahexaenoic acidand arachidonic acid. The preparation preferably contains at leastdocosahexaenoic acid. For cardiovascular-associated neurologicaldisorders such as dementia eicosapentaenoic acid is also suitablypresent. The daily dose of Ω-3 polyunsaturated fatty acids is preferablyat least 120 mg, more preferentially at least 350 mg.

The total fat composition in the preparation must be such that theproportion of unsaturated fatty acids is relatively high, that is to saymore than 50% of the fat. The unsaturated fatty acids preferably do nothave a trans configuration, that is to say the proportion of unsaturatedfatty acids having a trans configuration is less than 0.8%, preferablyless than 0.5% based on the total amount of fat (weight). In addition,the preparation contains as little linoleic acid as possible.

The proportion of Ω-3 polyunsaturated fatty acids relative to theproportion of Ω-6 polyunsaturated fatty acids must be relatively high.This means that the ratio between Ω-6 fatty acids and Ω-3 fatty acids ispreferably less than 3, more preferentially less than 2, for example1.4.

Cholesterol can be present in the fat composition, for example in anamount of 0.5 to 5% (m/m) of the total amount of fat.

Such a fat composition ensures that the membrane of the cells, inparticular nerve cells, has good arrangement and a fluid nature, so thatin vivo membrane processes can take place efficiently after activationof the receptor.

The polyunsaturated fatty acids are preferably present in the form ofbound fatty acids, for example fatty acids bound to glycerol, such as inthe form of triglycerides, but also, and this is preferred, in the formof phospholipids.

Components which have a beneficial effect on total methionine metabolism(TMM) are understood to be the components as described in EP 0 891 719,which is included herein by reference. These components are selectedfrom vitamin B12 and precursors thereof, vitamin B6 and derivativesthereof, folic acid, zinc and magnesium. Preferably these components areselected from vitamin B12 and precursors thereof, vitamin B6 and folicacid. More preferably a combination of folic acid, vitamin B6 andvitamin B12 is used.

Suitable forms of vitamin B12 are cyanocobalamin, hydroxy-, adenosyl- ormethyl-cobalamin or mixtures thereof, which may or may not be bound tobinding proteins in such a way that these can be completely and easilyabsorbed in the small intestine. These substances are suitablyincorporated in the preparation in an amount such that it contains atleast 3 μg, preferably at least 10 μg and in particular 50 to 1000 μgcobalamin per daily dose of the product.

Folic acid must be present in an amount of at least 250 μg, inparticular 300 to 1500 μg, per daily dose of the product. Suitable formsare folinic acid, folic acid and methyl derivates thereof, in thenon-oxidised or oxidised form.

Pyridoxine or derivatives thereof, such as pyridoxamine or pyridoxal,can be used in the product as suitable sources of vitamin B6. At least 1mg vitamin B6, preferably 2 to 20 mg vitamin B6, per daily dose iscontained in the product.

In addition to Ω-3 polyunsaturated fatty acids and components which havea beneficial effect on methionine metabolism, the preparation accordingto the invention can also contain phospholipids. These are preferablyphosphatidylserine, phosphatidylinositol, phosphatidylcholine andphosphatidylethanolamine. Preferably a mixture of two or more of thesephospholipids is used, in particular a mixture that contains at leastphosphatidyl-choline and phosphatidylserine. The daily dose ofphospholipids is preferably at least 0.2 g, more preferentially at least1 g.

Another characteristic of the phospholipids is the fatty acid group ofthe phospholipids. These preferably have a composition corresponding tothe Ω-3 polyunsaturated fatty acids as described above. This can beachieved by using known interesterification techniques using crudephospholipid mixtures and ingredients rich in the suitable fatty acidsas the starting materials.

This can also be achieved by feeding birds with special fats, so thatthe phospholipid fraction obtained from their eggs has a fatty acidcomposition that is as similar as possible to the desired composition.Varieties of plants can also be genetically modified so that theycontain the active compounds in the correct amounts. An example of thisis genetically modified soya where the phospholipid fraction containsadditional EPA and/or DHA.

Phospholipids can be obtained from egg yolk or soya and can be isolatedusing known techniques, for example by acetone extraction and subsequentchromatographic techniques or adsorption methods. If required, syntheticphospholipid fractions can also be used, but this is not preferred.

Other substances which are preferably present in the preparation arecomponents selected from thiamine, pantothenic acid, carnitine, vitaminC, vitamin E, carotenoids, coenzyme Q10 and flavinoids.

Amongst these, carnitine is a preferred compound. This also includesfunctional equivalents of carnitine, such as salts thereof or alkanoyl-and acyl-camitines (acetyl-L-camitine). Carnitine can be incorporated inan amount of 0.1 to 3 g, preferably 0.2 to 1 g per daily dose. CoenzymeQ10 can be incorporated in an amount of 0.8 to 200 mg, preferably 5 to70 mg per daily dose.

In the preparation of the invention the components are preferablycombined with existing agents which increase the amount ofneurotransmitter in the synapse. These can be the neurotransmittersthemselves, but also derivates thereof, precursors of theneuro-transmitters and drugs that are used for this purpose, such asdrugs that inhibit the reuptake of the neurotransmitters released in thesynapse, such as the so-called serotonin-reuptake inhibitors, orsubstances that inhibit the metabolic conversion of theneurotransmitters, such as the cholinesterase inhibitors, monoamineoxidase inhibitors and decarboxylation inhibitors. Certain nucleotidesor precursors thereof also stimulate the formation of neurotransmitters.

Examples of the neurotransmitters themselves are, for example, dopamineand the known analogues thereof which are already widely used incombating the symptoms of Parkinson's disease. These substances areobtainable in synthetic form. When the preparation of the invention isused, the dosage of these substances can be reduced by as much as 50%.

Known drugs that increase the levels of neurotransmitters, for exampleserotonin agonists or serotonin reuptake inhibitors, which can becombined with the preparation of the invention are Prozac, Zoloft,Luvox, Redux, Pondimin, Maxalt, Imitrex, Almogram, Zelapar, Selegiline,Mirapex, Permax, Exelon, Remilnyl, Aricept, Cognex, Tasaclidine, Ergosetand many other similar drugs. Insulin is also used to stimulate theinsulin receptor.

Other examples of neurotransmitters are serotonin, adrenaline,noradrenaline, glutamate, acetylcholine and gamma-aminobutyric acid.These can also be incorporated in the preparation.

Examples of precursors of neurotransmitters are the amino acidsL-tryptophan, L-phenyl-alanine and L-tyrosine. Under certain conditions,serotonin can be formed from L-tryptophan in the body of the animal.Also, for example, dopamine, noradrenaline (norepinephrine) andadrenaline (epinephrine) can be formed under certain conditions fromL-phenylalanine and/or L-tyrosine.

Functional equivalents of these amino acids can also be used asprecursor for neuro-transmitters, such as, for example, N-alkylatedforms or esterified forms and salts. An example of a suitable derivativeof tryptophan is 5-hydroxytryptophan. However, it is preferable to useproteins or hydrolysed products thereof or peptides. Preferably, theproteins used contain a relatively high concentration of the relevantamino acids. Enriched proteins can also be used, for example obtained bydialysis and membrane filtration techniques. An example of a proteinenriched in tryptophan is α-lactalbumin.

The amounts of neurotransmitters or agents which increase theconcentration of neuro-transmitters in the synapse are dependent on thenutritional status of the patient and his or her diet. Per daily dose,at least 14 mg/kg body weight phenylalanine+tyrosine, that is to say onaverage 1 g/day, must be consumed via the complete diet. The productaccording to the invention preferably contributes at least 50% to this,that is to say at least 0.5 g/day and preferably 0.7-3 g/day. The dietmust also provide at least 3.5 mg/kg body weight tryptophan. The productaccording to the invention preferably contributes at least 50% of this,that is to say at least 130 mg/day. Preferably the preparation contains200-2200 mg tryptophan per daily dose.

Under certain conditions, acetylcholine can be formed from choline andbetaine. Choline can also originate from phosphatidylcholine. It isadvantageous that the product contains at least 0.4 g cholineequivalents per daily dose, preferably in the form of 0.4 to 2 g betaineor in the form of 3.5 to 18 g phosphatidylcholine, in particularobtained from lecithins with rapeseed, egg or soya as possible source.

Nucleotides play an important role in the formation of acetylcholine. Itis preferable to incorporate nucleotides in the preparation, inparticular in the form of ribonucleic acids such as, for example, arepresent in yeast or extracts thereof. Preferably the product contains atleast 50 mg nucleobases, including uridine or cytidine, per daily dose.This corresponds to, for example, at least 2.5 g crude brewer's yeast.Instead of the bases it is also possible to use the phosphates thereof,such as the mono-, di- or tri-phosphate (for example uridinemonophosphate (UMP)).

A pentose, such as D-ribose, xylitol, L-arabinose or an oligosaccharideor polysaccharide that contains these sugars can also be incorporated inthe product instead of or in addition to nucleotides. Oligosaccharidesthat contain D-ribose and arabans are most preferred. At least 0.5 g ofthe pentose, preferably 1 to 20 g, is administered per daily dose.

The preparations according to the invention can be used for improvingthe action of receptors in cells of the central nervous system, inparticular for improving the sensitivity of receptors toneurotransmitters. Specific receptors that can be influenced by thepreparation of the invention are metabotropic receptors, preferably Gprotein coupled receptors.

Examples of metabotropic receptors are the seven transmembrane domainreceptors which usually function via G proteins, but also singletransmembrane domain receptors such as the tyrosine kinase receptorfamily (growth factors, insulin), the cytokine receptor family (growthhormone, erythropoietin, leptin, prolactin), the serine-threonine kinasereceptor family (TGF-beta), the guanylyl cyclase receptor family (atrialnatriuretic peptides) and the phosphotyrosine phosphatase family.

Disorders of which the severity can be reduced by increasing the actionof the receptor are, in particular, disorders associated with disturbedneurotransmitter functioning. Specific examples of these are Parkinson'sdisease, Huntington's chorea, epilepsy, schizophrenia, paranoia,depression, sleep disorders, impaired memory function, psychoses,dementia and ADHD and motor disorders such as can arise after, forexample, a trauma, stroke and ALS and chronic fatigue syndrome.

In view of the general nature of the improvement in receptor function,in a number of cases it is desirable to add an antagonist. This is, forexample, the case when aiming for weight loss. A more rapid effect isobtained if an antagonist for the α-2 receptor is given.

The preparation of the invention can be used both for humans andanimals, preferably for humans.

The preparation can be brought into a suitable form and administeredeither as a pharmaceutical preparation or as a nutritional preparation.Suitable additives and excipients for such preparations are known tothose skilled in the art.

EXPERIMENTAL

The chronic dietary intake of essential polyunsaturated fatty acids canmodulate learning and memory processes by being incorporated intoneuronal and glial plasma membranes. Representatives of the twoimportant polyunsaturated fatty acid families, the n−3 and n−6 typesbecome integrated into membrane phospholipids, where the actual(n−6)/(n−3) ratio can determine membrane fluidity. In the presentexperiment we studied hippocampal neurotransmitter receptor densitiesafter chronic administration of diets enriched indocosahexaenoic/eicosapentaenoic acid and methionine metabolismstimulating components in a brain hypoperfusion model which mimicsdecreased cerebral perfusion as it occurs in ageing and dementia.

Sixty 30-day-old Wistar rats were randomly divided into 3 groups of 20.Each group was given a specific diet, the first ordinary chow (placebo),the second group chow of a specific composition S1 and the third groupthe same feed as Group 2 with additional components (S2); see Table 1.The diets contained identical quantities of proteins, carbohydrates,minerals and energy. At the age of 4 months, two of the four carotidarteries of half of each group of animals were occluded (2VO animals).The other half was subjected to a similar operation without occlusion ofthe arteries. At the age of 7 months the animals were sacrificed forfurther investigation. Inter alia, the receptor density in specificparts of the brain was determined with the aid of labelling using aradioactive marker substance. Three receptor types, the muscarinic 1,serotonergic 1A and the glutaminergic NMDA receptors were labelled inhippocampal slices by autoradiographic methods. The increased ratio ofn−3 fatty acids in combination with additional dietary supplements(table 1) enhanced the density of the serotonergic 1A and muscarinic 1receptors (Table 2), but no major effects were found on the NMDAreceptors. Since the examined receptor types reacted differently to thedietary supplementation, it can be concluded that besides changes inmembrane fluidity, the biochemical regulation of receptor sensitivitymay also play a role in increasing hippocampal receptor density. TheNMDA receptor differs from the here investigated Ml and 5-HT1A receptorsin that the NMDA receptor is an ion channel receptor versus the othertwo G protein-coupled, metabotropic receptors. NMDA receptors areionotropic receptors which need no major conformational changes like themetabotropic receptors during binding. Metabotropic receptors like themuscarinic 1 acetylcholine receptor and the serotonergic 5-HT1 receptorbind transmitter and through a series of conformational changes bind toG proteins and activate them. These conformations are facilitated whenmembranes are fluid.

TABLE 1 Placebo S1 S2 Component g/100 g g/110 g g/110 g EPA — 0.5 0.5DHA — 0.37 0.37 ALA 0.155 0.137 0.184 LA 0.640 1.321 1.661 AA — 0.2 0.2β-carotene — 0.02 0.02 Flavonoids — 0.2 0.2 Folate 0.000784 0.001 0.001Selenium 0.000019 0.00004 0.00004 Vitamin B6 0.00153 0.00172 0.00172Vitamin B12 0.00005 0.00012 0.00012 Vitamin C — 0.2 0.2 Vitamin E 0.00630.3 0.3 Acetylcarnitine 0.6 Choline 0.4 Phosphatidylcholine 0.2Phosphatidylserine 0.2 Q10 0.03 Thiamine 0.002 0.2 Tyrosine 0.944 1Tryptophan 0.232 1

TABLE 2 (nCi/mg tissue) Acetylcholine receptor stratum Serotoninreceptor oriens Stratum radiatum Stratum oriens stratum radiatum Placebo2.8 3.1 7.3 9.6 S1 3.2 3.6 7.8 10.8 S2 3.3 3.7 8.5 11.6

1. A method for improving the efficacy of medication with a drug thatincreases the amount of neurotransmitter in the synapse, comprisingadministering to a subject medicated with said drug an effective amountof a composition comprising: a. ω-3 polyunsaturated fatty acidscomprising docosahexaenoic acid; b. at least one of: i. folic acid, ii.one or more of vitamin B6, pyridoxine, pyridoxamine and pyridoxal, andiii. a form of vitamin B12; and c. at least one of cytidine, uridine,and phosphates thereof.
 2. The method according to claim 1, wherein saidω-3 polyunsaturated fatty acids further comprise eicosapentaenoic acid.3. The method according to claim 1, wherein said composition comprisesfolic acid, which is preferably administered in a daily dose amount ofat least 250 μg.
 6. The method according to claim 1, wherein saidcomposition comprises one or more of vitamin B6, pyridoxine,pyridoxamine and pyridoxal, which is preferably administered in a dailydose amount of at least 1 mg of one or more of vitamin B6.
 7. The methodaccording to claim 1, wherein said composition comprises vitamin B12,which is preferably administered in a daily dose amount of at least 3 μgcobalamin equivalents.
 8. The method according to claim 1, wherein atleast one of cytidine, uridine and/or phosphates thereof areadministered in a daily dose amount of at least 50 mg.
 9. The methodaccording to claim 8, wherein said composition comprises uridine and/orphosphates thereof, which are administered in a daily dose amount of atleast 50 mg.
 10. The method according to claim 1, wherein said ω-3polyunsaturated fatty acids are administered in a daily dose amount ofat least 120 mg.
 11. The method according to claim 10, wherein said ω-3polyunsaturated fatty acids are administered in a daily dose amount ofat least 350 mg.
 12. The method according to claim 1, wherein saidcomposition further comprises at least one of zinc and magnesium. 13.The method according to claim 1, wherein said composition furthercomprises phospholipids in a daily dose amount of at least 0.2 g. 14.The method according to claim 1, wherein said composition furthercomprises a daily dose amount of at least 0.5 g of the sum of tyrosineand phenylalanine.
 15. The method according to claim 1, wherein saidcomposition further comprises tryptophan in a daily dose amount of atleast 130 mg.
 16. The method according to claim 1, wherein said drugthat increases the amount of neurotransmitter in the synapse is selectedfrom neurotransmitters, neurotransmitter derivatives, serotoninagonists, serotonin-reuptake inhibitors, cholinesterase inhibitors,monoamine oxidase inhibitors and decarboxylation inhibitors.
 17. Themethod according to claim 16, wherein said neurotransmitter is selectedfrom dopamine, noradrenaline and adrenaline.
 18. The method according toclaim 1, wherein said drug that increases the amount of neurotransmitterin the synapse is selected from fluoxetine, sertraline, fluvoxamine,dexfenfluramine, fenfluramine, rizatriptan, sumatriptan, almotriptan,seleginine, pramipexole, pergotide, rivastigmine, galantamine,donepezil, tacrine, tasaclidine, and bromocriptine.
 19. A method forreducing the severity of a disorder associated with disturbedneurotransmitter functioning, comprising administering to a subject inneed thereof an effective amount of a composition comprising: a. ω-3polyunsaturated fatty acids comprising docosahexaenoic acid; b. at leastone of: i. folic acid, ii. one or more of vitamin B6, pyridoxine,pyridoxamine and pyridoxal, and iii. a form of vitamin B12; c. at leastone of cytidine, uridine, and phosphates thereof; and d. a drug thatincreases the amount of neurotransmitter in the synapse.
 20. The methodaccording to claim 19, wherein said reducing the severity of a disordercomprises activation of receptors.
 21. The method according to claim 19,wherein said drug that increases the amount of neurotransmitter in thesynapse is selected from neurotransmitters, neurotransmitterderivatives, serotonin agonists, serotonin-reuptake inhibitors,cholinesterase inhibitors, monoamine oxidase inhibitors anddecarboxylation inhibitors.
 22. The method according to claim 21,wherein said neurotransmitter is selected from dopamine, noradrenalineand adrenaline.
 23. The method according to claim 19, wherein said drugthat increases the amount of neurotransmitter in the synapse is selectedfrom fluoxetine, sertraline, fluvoxamine, dexfenfluramine, fenfluramine,rizatriptan, sumatriptan, almotriptan, seleginine, pramipexole,pergotide, rivastigmine, galantamine, donepezil, tacrine, tasaclidine,and bromocriptine.
 24. The method according to claim 19, wherein saiddisorder associated with disturbed neurotransmitter functioning isselected from Parkinson's disease, Huntington's chorea, epilepsy,schizophrenia, paranoia, depression, sleep disorders, impaired memoryfunction, psychoses, dementia, ADHD and motor disorders.
 25. The methodaccording to claim 19, wherein said ω-3 polyunsaturated fatty acidsfurther comprise eicosapentaenoic acid.
 26. The method according toclaim 19, wherein said composition comprises folic acid which ispreferably administered in a daily dose amount of at least 250 μg. 27.The method according to claim 19, wherein said composition comprises oneor more of vitamin B6, pyridoxine, pyridoxamine and pyridoxal, which ispreferably administered in a daily dose amount of at least 1 mg of oneor more of vitamin B6.
 28. The method according to claim 19, whereinsaid composition comprises vitamin B12, which is preferably administeredin a daily dose amount of at least 3 μg cobalamin equivalents.
 29. Themethod according to claim 19, wherein said cytidine, uridine and/orphosphates thereof are administered in a daily dose amount of at least50 mg.
 30. The method according to claim 29, wherein said compositioncomprises uridine and/or phosphates thereof, which are administered in adaily dose amount of at least 50 mg.
 31. A combination comprising: a. adrug that increases the amount of neurotransmitter in the synapse b. ω-3polyunsaturated fatty acids comprising docosahexaenoic acid; c. at leastone of: i. folic acid, ii. one or more of vitamin B6, pyridoxine,pyridoxamine and pyridoxal, and iii. a form of vitamin B12; and d. atleast one of cytidine, uridine, and/or phosphates thereof.
 32. Thecombination according to claim 31, wherein said ω-3 polyunsaturatedfatty acids further comprise eicosapentaenoic acid.
 33. The combinationaccording to claim 31, wherein folic acid is present in a daily doseamount of at least 250 μg.
 34. The combination according to claim 31,wherein one or more of vitamin B6, pyridoxine, pyridoxamine andpyridoxal is present in a daily dose amount of at least 1 mg of one ormore of vitamin B6.
 35. The combination according to claim 31, whereinvitamin B12 is present in a daily dose amount of at least 3 μg cobalaminequivalents.
 36. The combination according to claim 31, wherein at leastone of cytidine, uridine and/or phosphates thereof are present in adaily dose amount of at least 50 mg.
 37. The combination according toclaim 36, wherein uridine and/or phosphates thereof are present in adaily dose amount of at least 50 mg.
 38. The combination according toclaim 31, wherein said ω-3 polyunsaturated fatty acids are present in adaily dose amount of at least 120 mg.
 39. The combination according toclaim 31, wherein said ω-3 polyunsaturated fatty acids, said at leastone of (i) folic acid; (ii) one or more of vitamin B6, pyridoxine,pyridoxamine and pyridoxal; (iii) a form of vitamin B12; and said atleast one of cytidine, uridine and/or phosphates thereof, are present ina single preparation.
 40. The combination according to claim 31, whereinsaid drug that increases the amount of neurotransmitter in the synapseis selected from neurotransmitters, neurotransmitter derivatives,serotonin agonists serotonin-reuptake inhibitors, cholinesteraseinhibitors, monoamine oxidase inhibitors and decarboxylation inhibitors.41. The combination according to claim 40, wherein said neurotransmitteris selected from dopamine, noradrenaline and adrenaline.
 42. Thecombination according to claim 31, wherein said drug that increases theamount of neurotransmitter in the synapse is selected from fluoxetine,sertraline, fluvoxamine, dexfenfluramine, fenfluramine, rizatriptan,sumatriptan, almotriptan, seleginine, pramipexole, pergotide,rivastigmine, galantamine, donepezil, tacrine, tasaclidine, andbromocriptine.